One of the unmet AIDS related needs NIAID has identified is Novel approaches to produce or release infection-blocking processes or agents in vivo, including at relevant mucosal sites. The current approach to prevention of HIV infection includes vaccines, male circumcision, partner reduction, and topical microbicides. Although very promising, topical microbicides have obstacles to overcome. They must achieve long-term protection and coitus-independent administration if they are to become an accepted HIV prophylactic in real world conditions. The specific problem is that adequate release durations and rates of biologically active microbicides formulated for vaginal delivery are often limited by microbicide molecular properties and/or variability in vaginal pH and hydration. We are a multidisciplinary consortium of university and industry scientists from drug delivery, microbicide development, and HIV/AIDS prevention research who offer a highly innovative tactic to solve this problem. Our hypothesis is that biologically inert, subliming-solids-based matrices (patent pending) could offer for the first time safe, controlled, and sustained intravaginal release of a wide array of fully active microbicide molecules, providing up to 30 days protection from HIV infection. We concomitantly expect formulated microbicide release and stability performance to be independent of their chemical properties, the local environment, and other agents, readily allowing development of combination products. Our specific aim is to test this hypothesis by determining the physicochemical and biological performance of subliming formulations for a critically chosen array of microbicides. We will investigate at least two representatives from each of four major molecular property classes: (1) low MW hydrophobic compounds, (2) low MW hydrophilic compounds, (3) oligomers and peptides, and (4) large denaturable proteins. Three major milestones will track our progress over four years of formulation design, preparation, and preclinical evaluation using in vitro, target cell culture, and ex vivo ectocervical explant models of human intravaginal environmental conditions. The Maskiewicz lab (Loma Linda University) will determine whether subliming microbicide formulations sustain desired release rates and stabilities in vitro for 7 days and 30 days within human intravaginal environmental limits. The Gallay lab (The Scripps Research Institute) will determine whether subliming microbicide formulations reduce HIV infection and replication in human primary target cell cultures over extended periods. And the Dezzutti lab (University of Pittsburgh) will determine whether the most promising subliming microbicide formulation from each major class sustains efficacy and safety in polarized human ectocervical explants. If project outcomes support the hypothesis, this bold, transformative approach could rapidly accelerate clinical evaluation of topical HIV microbicides by offering a universal solution for sustained and unobtrusive intravaginal administration. Prevention of sexual transmission of HIV is rendered difficult due to the large number of opportunities for infection (multiple acts of intercourse over several days), and often because of environmental & cultural inability of women to administer protection shortly prior to intercourse. Continuous and sustained intravaginal delivery of a single large dose of a HIV microbicide through a controlled release drug delivery system could provide continuous protection for prolonged periods prior to, during, and after each act of coitus, and would have a major impact on worldwide public health. We will therefore design and demonstrate a sustained release intravaginal drug delivery system which will be able to effectively deliver any and all microbicide drugs for weeks or months, in a manner independent of the timing of intercourse and independent of the potential range of clinical vaginal conditions.